A transient ischemic attack (“TIA” or “mini stroke”) is an acute episode of temporary neurologic dysfunction, typically lasting less than an hour (sometimes up to 24 hours). A TIA is caused by a brief interruption of oxygen flow or transient disturbance of blood supply to a tissue, typically due to an obstructing blood clot without infarction. When symptoms persist for a longer time and are accompanied by infarction, the dysfunction is categorized as a stroke.
Whereas the classical definition of TIA included symptoms lasting as long as 24 h, advances in neuroimaging have suggested that many such cases represent minor strokes with resolved symptoms rather than true TIAs. Thus, the American Heart Association and the American Stroke Association (ASA) endorse a tissue-based definition of TIA (i.e., as an episode of focal ischemia rather than acute infarction) rather than a time-based definition.
The most common cause of a TIA is an embolus (blood clot) that occludes an artery in the brain, and to a lesser extent, the spinal cord and retina. Typically, the clots result from an atherosclerotic plaque in one of the two carotid arteries, or from the heart, for example, in patients with atrial fibrillation (AFIB). Symptoms of TIA typically include temporary amaurosis (loss of vision), aphasia (difficulty speaking), hemiparesis (weakness of one side of the body, and/or paresthesia (numbness).
TIAs are often considered as a warning for an approaching stroke. Identification of TIAs is important as the incidence of a subsequent stroke is as high as 11% over the next 7 days and 24-29% over the following 5 years. However, up to 80% of strokes following TIA are preventable. Accordingly, early diagnosis and treatment are critical.
According to current guidelines of the American Stroke Association (ASA), risk factors include nonmodifiable factors (age, sex, race, and significant family history); modifiable factors (body weight, hypertension, unhealthy lipid profile, cerebral microbleeds, cardiovascular diseases, including coronary artery disease, myocardial infarction, peripheral arterial disease, valvular disease, atrial fibrillation, atrial flutter; diabetes mellitus; and lifestyle choices (cigarette smoking, alcohol consumption, illicit drug use, unhealthy diet/poor nutrition, and physical inactivity).
Patients with atrial fibrillation (AFIB) and atrial flutter (AFL) are at a higher risk for developing TIAs and strokes. AFIB affects about 2.3 million people in North America and 4.5 million people in the European Union and is emerging as a growing public health concern because of the aging of the population. AFIB is a condition in which the upper chambers of the heart beat in an uncoordinated and disorganized fashion, resulting in a very irregular and fast rhythm (i.e., an irregularly, irregular heartbeat). When blood is not completely pumped out of the heart's chambers, it can pool and clot. If a blood clot forms in the atria, exits the heart and blocks an artery in the brain, a TIA or stroke results. Consequently, about 15 percent of strokes result from AFIB.
AFL is a common abnormal heart rhythm, similar to AFIB, the most common abnormal heart rhythm. Both conditions are types of supraventricular (above the ventricles) tachycardia (rapid heartbeat). In AFIB, the heart beats fast and in no regular pattern or rhythm. By contrast, in AFL, the upper chambers (atria) of the heart beat abnormally fast, but in a regular pattern, resulting in atrial muscle contractions that are faster than and out of sync with the lower chambers (ventricles). AFL patients exhibit a distinct “sawtooth” pattern on an electrocardiogram (ECG), a test used to diagnose abnormal heart rhythms.
If left untreated, the side effects of AFIB and AFL can be potentially life threatening. With blood pooling in the heart (AFIB) or moving more slowly (AFL), it is more likely to form clots. If the clot is pumped out of the heart, it could travel to the brain, spinal cord, or retina, thereby causing a TIA or stroke.
TIAs and strokes represent different ends of an ischemic continuum from the physiological perspective, but clinical management is similar. In some cases, antiplatelet drugs have been found to be effective in preventing TIAs. Many physicians believe antithrombotic therapy should be initiated as soon as intracranial hemorrhage has been ruled out. For patients with TIA or ischemic stroke of cardiac origin due to atrial fibrillation, vitamin K antagonists (VKAs) are highly effective in preventing recurrent ischemic stroke but have important limitations and are consequently underused. Antiplatelet therapy is less effective than VKAs. The direct thrombin inhibitor, dabigatran etexilate, has shown efficacy over warfarin in a recent trial. Other anticoagulants include oral factor Xa inhibitors, such as rivaroxaban, apixaban, and edoxaban; the parenteral factor Xa inhibitor, idrabiotaparinux, and the VKA, tecarfarin.
Notwithstanding the risks for strokes in patients with AFIB and AFL, however, strokes mainly occur in patients without AFIB or AFL. In view of the foregoing, there is a need for improved medications for preventing TIAs and nerve injuries in patients at risk.